Sampson suggested that menstrual regurgitation and subsequent implantation of endometrial tissue on the peritoneal face results in endometriosis [Sampson, J. A. (1927), Peritoneal endometriosis due to menstrual dissemination of the endometrial tissue into the peritoneal cavity. Am. J. Obstet. Gynecol., 14, 422.]
Several aetiologic factors may be involved in the pathogenesis of endometriosis:
Dmowski et. al. suggested that genetic and immunological factors lead to endometriosis [Dmowski, W. P. Steele, R. W. and Baker, G. F. (1981). Deficient cellular immunity in endometriosis. Am. J. Obstet. Gynecol., 141, 377]
Vascular and lymphatic embolization to distant sites has been demonstrated and explains the (rare) finding of endometriosis outside the peritoneal cavity, e.g. skin, lung, kidney.
Cells lining the Mūllerian duct arise from primitive cells which differentiate into peritoneal cells and the cells on the surface of the ovaries. It is proposed that these adult cells undergo de-differentiation back to their primitive origin and then transform into endometrial cells [Levander, G. (1941), Bone formation by induction. An experimental study. Arch. Klin. Chir., 202, 497]
Dysmenorrhea, acute or chronic pelvic pain, dyspareunia, and infertility perform the most frequent clinical symptoms reported.
FTO represents a heterogenous group of underlying pathology, preliminary intrinsic occlusion or extrinsic compression from estrogen-sensitive disorders, such as endometriosis, adenomyosis, endosalpingiosis, and myomata. FTO is frequently diagnosed by hysterosalpingography, besides laparascopy.
First choice of treatment comprises laparoscopic removal of endometric lesions. This procedure may be followed by the treatment with Danazol or LHRH agonist (for a period of six months). Women being treated with Danazol might experience gastrointestinal and hepatic disorders as well as severe androgenic side effects.
It was also proposed from a theoretical viewpoint for treatment of endometriosis and uterine myoma to use the immediate suppression by administration of a LHRH antagonist to reducing the duration of treatment and faster improvement of subjective symptoms [Th. Reissmann et al. Human Reproduction vol. 10 No. 8 pp. 1974-1981, (1995)]
Further Hodgen teaches in the U.S. Pat. No. 5,658,884 a regime for therapeutic management of a gonadal dependent condition by reducing the estrogen supply by means of long-term administration of an GnRH antagonist for 6 months or longer in an amount effective to inhibit proliferation of endometrial tissue without substantially stopping the production of endogenous estrogen. For this purpose, Hodgen teaches such a regimen or dose of GnRH antagonist to achieve a 24 hour serum estradiol level in the range of about 25 to 50 and preferably about 35 to 45 pg/ml. However, Hodgen does not describe estradiol serum levels oscillating between 50 pg/ml and 75 pg/ml. Moreover, Hodgen only teaches in the U.S. Pat. No. 5,658,884 a continuous long-term treatment (on a daily or periodic basis, the latter meaning a weekly or monthly administration) but not a short-term induction treatment for only 4 to 12 weeks. Hodgen also does not describe any combination therapy comprising the GnRH antagonist in the treatment of endometriosis. The treatment is only described on monkeys and also includes the performance of a costly and repeated progesterone challenge test to provide an 24 hour average serum estradiol level of 30 to 50 pg/ml.
As a consequence of the flare-up effect of LHRH-agonistic therapy an exacerbation of symptoms might occur during some days. Following prolonged treatment which is required to avoid the re-proliferation of endometric tissue hormonal withdrawal symptoms as well as demineralization of bones occur.
Therefore, effective drug therapy should immediately reduce the residual extrauterine endometrial tissue present after laparoscopic surgery. Duration of therapy should be only 4 to 12 weeks without the occurrence of any major hormonal withdrawal symptoms or ovarian cyst formation.
LHRH antagonists exert an immediate onset of hormonal suppression, and therefore benign gynecological tumors, such as uterine fibroids decrease within short time [Human Reproduction 1998, 13]